title: Anti-MS4a4B treatment abrogates MS4a4B-mediated protection in T cells and ameliorates experimental autoimmune encephalomyelitis.
abstract: Recent data show that anti-CD20 therapy is effective for some autoimmune diseases, including multiple sclerosis (MS). However, the efficacy of anti-CD20 therapy for MS is largely limited because anti-CD20 antibodies target only B cells. In previous studies, we have investigated the function of MS4a4B, a novel CD20 homologue, in T cell proliferation. Here, we found that MS4a4B regulates not only T cell proliferation but also T cell apoptosis. Knockdown of MS4a4B by MS4a4B-siRNA or MS4a4B-shRNA-expressing vector promoted apoptosis in primary T cells and T32 cell line. In contrast, vector-driven over-expression of MS4a4B reduced apoptosis in EL-4 cells. Machinery analysis showed that MS4a4B-mediated T cell survival was associated with decreased activity of caspases 3, 8 and 9. Interestingly, binding of anti-MS4a4B antibodies to T cells induced activated T cells to undergo apoptosis. To test whether anti-MS4a4B antibody interferes with MS4a4B-mediated protection of T cells, we injected anti-MS4a4B antibodies into mice with experimental autoimmune encephalomyelitis (EAE). The results show that anti-MS4a4B treatment ameliorated the severity of EAE, accompanied by decreased Th1 and Th17 cell responses and reduced levels of pro-inflammatory cytokines in the central nervous system, suggesting that MS4a4B may serve as a target of antibody-based therapy for T cell-mediated diseases.
authors.affiliation: Department of Neurology, Thomas Jefferson University, 900 Walnut Street, JHN 300, Philadelphia, PA 19107, USA.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Yan
authors.forename: Zichen
authors.initials: Z
authors.lastname: Li
authors.forename: Guang-Xian
authors.initials: GX
authors.lastname: Zhang
authors.forename: Mark S
authors.initials: MS
authors.lastname: Williams
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Carey
authors.forename: Jianke
authors.initials: J
authors.lastname: Zhang
authors.forename: Abdolmohamad
authors.initials: A
authors.lastname: Rostami
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
mesh_terms: D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D017209:Apoptosis; D049109:Cell Proliferation; D016207:Cytokines / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000503:physiopathology*; D005260:Female; D055786:Gene Knockout Techniques; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology
chemical_list: D000906:Antibodies; D016207:Cytokines; D008565:Membrane Proteins; C411486:Ms4a4b protein, mouse; D034741:RNA, Small Interfering